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OK. I think we'll get started.
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So we're going to continue our
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discussion today about viruses,
finish talking about influenza,
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influenza A virus and the flu,
and then talk a bit about HIV and
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AIDS. Do you guys know more about
the tutorial session and so on and
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so forth for next week?
Has that been decided yet? OK.
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So you'll get more information
Monday and Wednesday.
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And I'll also have an office hour,
probably a couple of office hours at
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the end of next week.
Most likely, if it doesn't conflict
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with this tutorial session that's
being planned,
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it will be during this hour from
11:00 probably until 1:00 in this
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room because it's free since we're
usually here. But that may conflict
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with you guys so we'll have to see.
I'll let you know on Monday.
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So, again, the situation with
viruses is an ongoing one.
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And, actually, one of you brought
to my attention an outbreak of polio
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that's happening now both in Africa
and Indonesia.
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This is actually from today's CNN.
om where there's a fear that polio
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is starting to spread.
In this case in Jakarta,
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in Indonesia. And there's a very
extensive reaction to this.
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There's a great fear that polio
will spread.
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This is an area that is not well
protected currently by polio
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vaccination. And so if you look at
this you'll see that they are
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raising lots of money in order to
try to vaccinate with standard polio
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vaccines, which work extremely well,
5.2 million children, to try to stop
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the spread of this potential
epidemic of polio.
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It hasn't reached anything near
those levels to be that concerned,
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but in order to protect against that
possibility they're going
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to vaccinate.
And, obviously,
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if you vaccinate,
individuals cannot be successfully
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infected. If they cannot be
successfully infected,
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the virus cannot propagate so they
cannot pass it on.
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So you just close off the
infectious cycle in a very small
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circle of infected individuals.
Also, in today's Globe, there was a
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discussion of a local company that
makes vaccines against smallpox.
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And I've mentioned to you that
smallpox is largely eliminated,
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if not fully eliminated in the world,
but there are stocks of smallpox in
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freezers around the world.
And there is a concern that an
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individual could access smallpox
virus or make one because the
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relevant sequences of the genome of
the smallpox virus is known.
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And so, in theory, you could
synthesize your own smallpox virus
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genome, and thereby create your own
smallpox virus and expose now
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unprotected individuals because we
don't get vaccinated currently
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against smallpox.
And so there are companies like
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this one that are making currently
and distributing smallpox vaccines.
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They distributed 182 million doses
in this country alone just in case
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somebody tried to deliberately
release some smallpox.
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So that's what we can do when we
know what we're dealing with.
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We can create effective vaccines.
In this case they're effective, but
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sometimes we get exposed to stuff
that we cannot effectively deal with.
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And I introduced this
to you last time.
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This was the major flu pandemic from
1918. Some people worried that
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there might be another pandemic this
year because in the off season
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between 1918 and 1919 when this
happened, and 20 to 40 million
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people died, that's when the Red Sox
last won the World Series.
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[LAUGHTER] So the Armageddon folks
thought maybe this was the year,
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but so far so good. So, as I
mentioned last time,
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this was a major outbreak and a
major problem worldwide.
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But you also should know that
influenza is an annual problem.
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And I, for one, didn't appreciate
this.
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Where there are about 25 thousand
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deaths per year in the United States.
And, of course,
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to deal with that we make available,
especially to the elderly and
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infirmed immunodeficient flu shots.
And flu shots are simply flu
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vaccines. And I'll tell you a
little bit about how they're made
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towards the end of this section,
but they're generally effective in
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combating against the flu that is
going to hit the population that
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year. And they change every year
because, as you'll see,
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flu changes all the time as well.
So it's an annual problem. There
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are occasional epidemics which you
could think of as --
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-- population-based infection where
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many individuals within a particular
population are infected.
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And the virus, in this case,
is spreading throughout that
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population. And there are even more
occasional pandemics.
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And that's a worldwide infection.
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Where, because of the virulence of
the virus and its ability to access
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different populations and the
absence of immunity throughout the
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worldwide population,
lots and lots of people get infected.
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And that's what happened in 1918.
So how do we explain this? How do
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we explain the occasional epidemics
of a virus that we're so familiar
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with? Flu, as I said,
we get every year, lots of people
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get it every year.
And, yet, we seem to be susceptible
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year after year.
So why is that? What causes the
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resistance to this immunity in small
measure and in large measure?
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And that's what I want to review
for you today.
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So this is the responsible agent.
It's a virus, of course. More
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specifically, it's an enveloped
virus, which means it has its own
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lipid bilayer that it picked up from
the host cell.
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And you'll notice on the outside are
things sticking out of the bilayer.
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These are proteins encoded by the
virus which are going to be
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responsible for binding the virus to
the host cell.
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And also allowing the viral
membrane to fuse with the host cell
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membrane. And you'll see that
that's done in the case of flu virus
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in a slightly different way than for
some other viruses.
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And then inside you have the capsid.
And wrapped up in this protein,
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this helical protein structure are
the nucleic acids of the virus.
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And the nucleic acids of this virus
are multiple. That is it's not just
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one. Oops. It's not just one.
It's actually several.
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So, again, it's called influenza A
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virus. It's an example
of an enveloped virus.
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And I said you should note the
envelope proteins,
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which are largely encoded by the
virus itself. And we call these
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envelope glycoproteins.
Glycoproteins because when they
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emerge through the sorting pathway
of the cell they pick up sugars.
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And so when they're on the outside
of the cell, it's not just protein.
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There is some sugar there, so
glycoproteins.
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And sometimes the antibodies that
we make are directed against the
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sugar moieties alone or in
combination with peptides.
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So the envelope glycoproteins are
important. As I said,
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it's a segmented RNA genome,
which means that there are multiple
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distinct nucleic acids in the viral
particle. And in the case of flu
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there are eight.
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The RNA genome is single-stranded.
And all of the genome segments are
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in the minus configuration.
So their sequence is the complement
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to the mRNA. OK?
And we talked about the
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significance of RNA viruses that
have a minus strand polarity in the
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sense that they need to have their
own RNA polymerase coming in with
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the virus in order to help,
in order to initiate the replication
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cycle.
So, hopefully,
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that's familiar from last time.
This is a diagram of the virus,
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and it just makes the same points I
just made. So,
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again, it has a lipid bilayer.
It has envelope glycoproteins
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sticking out from the surface.
You'll see that they're important
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for different things in a moment.
Inside that is a nucleocapsid which
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surrounds the nucleic acids.
And you can see that there's a
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series of nucleic acids that are
enclosed within this.
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And, again, there are eight of them.
And they're all minus strand.
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And, importantly, contained within
here is a protein,
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an RNA dependent RNA polymerase,
the yellow dot. And it has to get
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incorporated with the virus so that
when the virus infects it goes in
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there, too. And it can then act on
the RNA genome and convert it into a
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plus strand, which will then serve
both as the RNA for translation,
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as well as the template for the
production of more of the
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minus strand RNA.
OK? So this comes from your book,
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and it is a summary of the
infectious cycle of this virus.
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I've modified it a little bit
because some of the details which I
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think are important were missing.
So you might want to pay attention
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to this figure as you're reading the
section, the relevant
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section in the book.
But this is a typical viral
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lifecycle. The virus attaches.
Remember, the terms that I used
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last time? The virus attaches.
Here one of the viral glycoproteins
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binds to a protein on the surface of
the target cell.
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That then initiates an
internalization process,
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a penetration process in which the
virus gets brought in through an
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endosome. So it gets brought in
through a separate vesicle,
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an endosome. That vesicle, the
endosome then fuses with a lysosome,
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not shown here.
And you may recall that the
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lysosomes have very low pH.
And it's in the context of the low
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pH that one of the viral
glycoproteins changes its shape.
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And when it changes its shape it
allows the viral membrane to fuse
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with the membrane of the lysosome.
So this is a pH-dependant protein
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conformational change which turns an
inner protein into a protein that
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facilitates fusion.
And when that happens,
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the viral capsid can then slip out
into the cytoplasm.
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It gets unpackaged.
The RNA, which is the minus strand
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RNA gets released.
And then it gets acted on by that
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RNA dependent RNA polymerase that
came in and gets converted from
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minus strand to plus strand.
And the plus strand can then do two
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things. It can get translated into
viral proteins,
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both the glycoproteins that go
through the sorting pathway and make
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it to the membrane,
as well as the structural proteins
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that form the capsid.
The structural proteins then join up
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with the viral RNA segments,
now the minus strand RNA segments.
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They meet at the membrane and then
bud off to form a new virus.
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OK? So this is a standard
infectious cycle for this class of
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viruses. And because it's going to
be relevant later,
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I just want to emphasize a couple of
points.
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Through interactions between the
cytoplasmic tail of the envelope
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glycoprotiens,
the capsid proteins coalesce
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underneath the plasma membrane.
And there's an interaction between
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these proteins and the tails of
these proteins which causes the
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virus to start to bud off the
surface of the cell.
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Now, there are separate interactions
with the proteins on the inside of
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the capsid which bring with them the
different viral RNA.
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So remember there are eight.
And there's a rather amazing
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process by which the eight distinct
RNA segments get brought together
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into the capsid,
and then the capsid goes to the
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membrane and gets budded.
So there is a sorting process,
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which we don't fully understand,
that ensures that viruses get at
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least one copy of each of the
genomic segments.
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And that's necessary because if a
virus doesn't have all eight,
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when it gets into the host cell that
it might infect,
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it's not going to be able to
replicate. These RNA segments
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encode one, or at most two of the
viral proteins that are necessary
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for the infectious cycle that's
drawn up there.
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And you'll see why that's important
in a moment.
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OK. So we get infected,
we develop antibodies against the
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proteins of the virus,
and we typically develop them
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against the glycoproteins that are
sitting on the outside.
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We develop T cells that can
recognize virus infected cells and
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kill them. And yet we keep getting
flu. So why is that?
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How is it that we can,
how is it that the virus can
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overcome this immune resistance?
And the answer is that the virus
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changes. And this is a major
problem with all viruses,
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but it's a particular problem with
RNA viruses and a particular problem
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with flu. So here's a depiction of
the virus again.
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It's got its genomic segments in
here. And on the surface it has
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these glycoproteins.
And I'm going to draw a little bit
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more detail in these
glycoproteins now.
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There are actually two distinct
glycoproteins on the surface of the
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cell. There's one that's called HA
and there's another that's called NA.
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And they carry out different
functions. When you get infected,
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your immune system sees these
epitopes sitting on the surface of
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the virus and you make antibodies
against them. And there are three
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particular places on these proteins
where good antibodies can be made
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inside your body.
One of them is here,
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another one is here, and a third one
is here. And different people make
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different of these antibodies.
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And these antibodies that are made
have a name which is neutralizing or
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blocking antibodies.
They're called that because if you
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have one of these antibodies,
and it will bind to the surface of
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the viral particle,
this virus can now not infect the
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cell. There's an interference
between the, what the hell?
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Between the glycoproteins on the
surface and the receptors to which
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they bind by the antibody.
So they block binding. And if you
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cannot bind you cannot infect.
And this is very efficient. This
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works. So that's how you can
overcome the infection to that
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particular virus.
The problem is that viruses change.
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During their replication there are
mutations.
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And sometimes these mutations affect
the structure of the proteins that
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are sitting on the surface.
So you might imagine the strain
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here gives rise to variant here
which has an HA protein which looks
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more or less the same,
but it has an NA protein which has
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changed. So now this epitope,
which was recognized by antibody
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three, cannot be recognized by
antibody three because it's got a
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difference sequence.
OK? If you were a person who made
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predominantly antibody three in
response to this infection,
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you would not be susceptible to this
virus. So if this one came along
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next year you'd get the flu.
If you were a person who made
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antibody one or antibody two as your
major protective antibody,
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you'd still be resistant to this.
You'd be one of the lucky ones.
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And because there's heterogeneity
within our population,
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even if these new variants arise,
they don't spread all that much
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because there are enough people in
the population who are pretty well
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protected. So those are low-level
spread or low-level epidemics.
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OK? Now, this process, one day I'm
going to figure out how this works.
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This process of generating variant
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viruses through this mutational
mechanism is called
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antigenic drift.
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It's a slow drift of the antigens on
the virus. And it happens because
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the virus is highly mutagenic.
And it's true of RNA viruses in
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general.
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And there are two reasons why RNA
viruses create variants at such high
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levels. One is that RNA is less
stable than DNA.
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Remember, there's a difference in
the structure of RNA versus DNA.
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There's an extra hydroxyl in the
structure of RNA which can cause
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increased mutation,
increased breaks and base
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substitutions in our RNA molecules
compared to DNA molecules.
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So RNA is inherently less stable
than DNA. And also RNA polymerases
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lack proofreading functions.
250
00:20:25 --> 00:20:30
Which means they have an inherently
higher mutation rate.
251
00:20:30 --> 00:20:34
And hopefully,
again, this is familiar from our
252
00:20:34 --> 00:20:38
discussions about DNA replication.
All polymerases make mistakes but
253
00:20:38 --> 00:20:42
your DNA polymerases have what's
called a proofreading function which
254
00:20:42 --> 00:20:46
can recognize the mistakes and
correct them. RNA polymerases lack
255
00:20:46 --> 00:20:50
that, and so they make the mistakes
and they stay as mistakes.
256
00:20:50 --> 00:20:54
So the mutation rates for RNA
polymerases are at least ten fold
257
00:20:54 --> 00:20:58
higher than for DNA polymerases,
and in some places even higher still.
258
00:20:58 --> 00:21:02.25
OK.
So that's what's called antigenic
259
00:21:02 --> 00:21:06.75
shift, sorry, antigenic drift.
And it happens all the time and is
260
00:21:06 --> 00:21:11.25
responsible for why we keep getting
mild cases of the flu.
261
00:21:11 --> 00:21:15.75
But that's not what's responsible
for the Spanish flu of 1918.
262
00:21:15 --> 00:21:23
Instead of antigenic drift --
263
00:21:23 --> 00:21:27
-- these are due to a phenomenon
called antigenic shift.
264
00:21:27 --> 00:21:31
Rather than generating subtly
different variants,
265
00:21:31 --> 00:21:35
like I've shown up here,
this is the process of generating
266
00:21:35 --> 00:21:47
essentially entirely new strains.
267
00:21:47 --> 00:21:50
And it happens in the case of flu
all the time. And one of the
268
00:21:50 --> 00:21:54
reasons that it happens is that
there are lots and lots of types of
269
00:21:54 --> 00:21:58
flu viruses which are kind of
similar that infect other species.
270
00:21:58 --> 00:22:02
There are duck flus,
swine flus, horse flus,
271
00:22:02 --> 00:22:07
seal flus that are all caused by
versions of this influenza A virus.
272
00:22:07 --> 00:22:12
Similar. Not identical but similar.
And sometimes those viruses cross
273
00:22:12 --> 00:22:17
over into the human population.
And this is an example of a
274
00:22:17 --> 00:22:35
zoonotic infection --
275
00:22:35 --> 00:22:38
-- which is an infection from
another species into the human
276
00:22:38 --> 00:22:41
population. And actually happens
all the time. Many of the new
277
00:22:41 --> 00:22:44
pathogens that arise in the human
population arise through zoonotic
278
00:22:44 --> 00:22:47
infection. Now,
most viruses that are evolved to
279
00:22:47 --> 00:22:50
grow in the cells of one given
species, at the temperature of a
280
00:22:50 --> 00:22:54
given species,
will not replicate very well inside
281
00:22:54 --> 00:22:57
human cells. So even if they did
infect, they wouldn't reproduce
282
00:22:57 --> 00:23:01
themselves very well.
And that would be true of these
283
00:23:01 --> 00:23:06
viruses, too, swine flu virus,
bird flu viruses. The problem is,
284
00:23:06 --> 00:23:10
in the case of flu, the human virus
is so common and the mechanism of
285
00:23:10 --> 00:23:15
replication of this virus is so
complex and amenable to generation
286
00:23:15 --> 00:23:20.46
of recombinant viruses that we can
generate new viral forms.
287
00:23:20 --> 00:23:25.23
And that's what I want to talk to
you about now.
288
00:23:25 --> 00:23:30
So here's an example from not too
long ago.
289
00:23:30 --> 00:23:34
This is the collection and culling
of a lot of birds somewhere in Asia.
290
00:23:34 --> 00:23:39
I'm not really sure where this was.
But there was a concern that a new
291
00:23:39 --> 00:23:44
virus was developing in a bird
population and was crossing over
292
00:23:44 --> 00:23:49
into humans. And it caused some
deaths. And so to avoid that
293
00:23:49 --> 00:23:54
further they just wiped out some
millions of these birds in order to
294
00:23:54 --> 00:23:59
prevent further cross infection.
But, again, it's not the presence of
295
00:23:59 --> 00:24:04
the virus, the bird virus or swine
virus itself that's the problem.
296
00:24:04 --> 00:24:08
It's the fact that the two viruses,
the human virus and the bird virus
297
00:24:08 --> 00:24:13
can recombine to form a dangerous
new virus which is rather similar to
298
00:24:13 --> 00:24:18
the human virus but carries some
segments of the bird virus.
299
00:24:18 --> 00:24:22
And that's illustrated here,
and I'll show you on the board in a
300
00:24:22 --> 00:24:27
second. But basically the idea is
that a human virus carrying its
301
00:24:27 --> 00:24:32
eight segments,
including the segment for HA and NA
302
00:24:32 --> 00:24:37
infects an animal which also gets
infected by a bird virus.
303
00:24:37 --> 00:24:41
So that in the same cell there are
the segments for the human virus,
304
00:24:41 --> 00:24:45
as well as the segments for the bird
virus. And during this process of
305
00:24:45 --> 00:24:49
the generation of a new viral
particle, you can get mixing of the
306
00:24:49 --> 00:24:53
segments so that most of the
segments come from the human virus
307
00:24:53 --> 00:24:57
and, therefore,
will replicate well in the context
308
00:24:57 --> 00:25:02
of the human cell.
But two new segments come in from
309
00:25:02 --> 00:25:08
the bird that encode its HA and NA,
a version that's never been seen in
310
00:25:08 --> 00:25:13
the human population.
Nobody has antibodies against it so
311
00:25:13 --> 00:25:18
the virus can spread like wildfire.
And that's what we believe happened
312
00:25:18 --> 00:25:24
then and we fear continues to happen
over time. So,
313
00:25:24 --> 00:25:29
again, imagine a cell which has been
infected by two different viruses,
314
00:25:29 --> 00:25:35
the avian virus, in this case it was
a duck, as well as the human virus
315
00:25:35 --> 00:25:41
in that given year.
In that cell there are going to be
316
00:25:41 --> 00:25:47
lots of different segments of virus
RNA, the human ones H1,
317
00:25:47 --> 00:25:53
2, 3, 4, 5, 6, 7, 8 and so on,
as well as the duck ones, duck 1,
318
00:25:53 --> 00:25:59
duck 2 and so on and so forth, duck
7 and duck 8.
319
00:25:59 --> 00:26:05
When the viral capsids coalesce
underneath the viral glycoproteins
320
00:26:05 --> 00:26:12
to produce a new virus,
they cannot necessarily distinguish
321
00:26:12 --> 00:26:19
between the human and the duck
subunits. So there might be human 1,
322
00:26:19 --> 00:26:26
human 2, human 3,
duck 4, human 5, duck 6,
323
00:26:26 --> 00:26:32
human 7 and human 8.
OK? This then makes a virus which
324
00:26:32 --> 00:26:36
is perfectly able to replicate in
human cells because it's got mostly
325
00:26:36 --> 00:26:40
the genes that are optimized for
human cells, but it's got new HA and
326
00:26:40 --> 00:26:44
NA forms that have never been seen
by the human population.
327
00:26:44 --> 00:26:49
So there is nobody who has
antibodies against it.
328
00:26:49 --> 00:26:53
So the virus will spread like crazy.
OK? So this is an example of
329
00:26:53 --> 00:26:57
antigenic shift,
and it's responsible for these
330
00:26:57 --> 00:27:01
worldwide pandemics.
OK. Any questions about flu?
331
00:27:01 --> 00:27:05
One thing I failed to mention,
sort of trivial but you probably
332
00:27:05 --> 00:27:09
know, is it spread very well because
it can spread in water droplets.
333
00:27:09 --> 00:27:13
If you sneeze on your friends
they'll also get the flu.
334
00:27:13 --> 00:27:17
It's a very efficient virus so you
don't need very many viral particles
335
00:27:17 --> 00:27:21
to go inside of your respiratory
system in order to initiate the
336
00:27:21 --> 00:27:25
infection. And this is another good
example. When you have a very
337
00:27:25 --> 00:27:29
active infection inside of you,
you start producing lots of the
338
00:27:29 --> 00:27:33
cytokines, that I mentioned last
time, like interferons.
339
00:27:33 --> 00:27:37
And, again, it's largely those that
are causing the symptoms of the flu,
340
00:27:37 --> 00:27:41
and in large enough quantities can
cause death. You can also get
341
00:27:41 --> 00:27:45
secondary infections with bacteria
when you're that sick,
342
00:27:45 --> 00:27:49
which can be another reason why
folks die. OK.
343
00:27:49 --> 00:27:53
So if there are no other questions
about flu, we'll now turn our
344
00:27:53 --> 00:27:57
attention to HIV.
And I think HIV is probably fairly
345
00:27:57 --> 00:28:02
familiar as a topic.
It's, of course,
346
00:28:02 --> 00:28:08
a major, major worldwide health
problem. The initiation of this
347
00:28:08 --> 00:28:18
epidemic goes back a very long way.
348
00:28:18 --> 00:28:24
The first cases were reported in
1975, so about 30 years ago.
349
00:28:24 --> 00:28:30
And so that's considered to be the
initiation of this epidemic
350
00:28:30 --> 00:28:35
or pandemic.
The first case in the United States
351
00:28:35 --> 00:28:39
is considered to have occurred in
1980. And here's another example.
352
00:28:39 --> 00:28:43
We think that this probably
occurred by one of the
353
00:28:43 --> 00:28:51
zoonotic infections.
354
00:28:51 --> 00:28:55
But it happened a long time ago.
It happened at least before 1950
355
00:28:55 --> 00:28:59
because there are samples of
individuals who died of unknown
356
00:28:59 --> 00:29:03
causes that have now been tested and
can be shown to have HIV
357
00:29:03 --> 00:29:08
sequences by PCR.
So whenever this happened,
358
00:29:08 --> 00:29:12
and from whatever species it
happened, it happened quite a while
359
00:29:12 --> 00:29:17
ago. Why it then initiated in this
epidemic form much later is not so
360
00:29:17 --> 00:29:26
clear. The etiological agent --
361
00:29:26 --> 00:29:33
-- is a virus called HIV,
human immunodeficiency virus.
362
00:29:33 --> 00:29:37
It is a retro virus.
And we'll briefly review how it
363
00:29:37 --> 00:29:41
replicated, but I told you more or
less how that happens last time.
364
00:29:41 --> 00:29:46
And this was another good example.
The syndrome was first discovered
365
00:29:46 --> 00:29:50
in 1975, gained a lot of attention
in this country starting in the
366
00:29:50 --> 00:29:55
early 1980s, and the virus was first
purified and characterized in 1983.
367
00:29:55 --> 00:29:59
So it didn't take too long to
identify the agent and then
368
00:29:59 --> 00:30:04
ultimately sequence its genome.
And also to develop tests for the
369
00:30:04 --> 00:30:10
presence of actually not the virus
itself. The AIDS test is a test for
370
00:30:10 --> 00:30:15
the presence of antibodies in you
that recognize the viral
371
00:30:15 --> 00:30:21
glycoproteins.
And this was very important,
372
00:30:21 --> 00:30:27
obviously, in screening populations,
screening blood banks and so on for
373
00:30:27 --> 00:30:32
contaminated samples.
Now, since this time,
374
00:30:32 --> 00:30:36
in the early 1980s, the situation
has, of course,
375
00:30:36 --> 00:30:40
gotten much, much worse.
In this country, there are
376
00:30:40 --> 00:30:52
currently --
377
00:30:52 --> 00:30:56
-- a million people infected with
HIV. That's between,
378
00:30:56 --> 00:31:00
you know, one and 300 individuals
total.
379
00:31:00 --> 00:31:08
And, amazingly,
about 20% of those people don't know
380
00:31:08 --> 00:31:16
it. Worldwide,
anybody have any idea how many
381
00:31:16 --> 00:31:24
people are infected with HIV in the
world? 40 million.
382
00:31:24 --> 00:31:32
And total about 60 million people
have been infected because since the
383
00:31:32 --> 00:31:40
early 1980s, 20 million people have
died from this disease.
384
00:31:40 --> 00:31:45.75
More than 20 million.
And the prevalence is remarkable in
385
00:31:45 --> 00:31:51.5
certain places in the world.
In Southern Africa, for example,
386
00:31:51 --> 00:31:57.25
not the country of South Africa but
in the Southern Region of Africa,
387
00:31:57 --> 00:32:03
Saharan Africa, there are 25 million
people infected.
388
00:32:03 --> 00:32:08.5
And in certain countries that's one
in four sexually active individuals.
389
00:32:08 --> 00:32:14
Remarkable infection rates. And
the effect of this disease and the
390
00:32:14 --> 00:32:19.5
death that it causes has also had
dramatic effects on the population.
391
00:32:19 --> 00:32:25
So that in Zimbabwe, for example,
where the life expectancy in 1990
392
00:32:25 --> 00:32:30.5
was 52 years old,
not a huge number but 52 years old,
393
00:32:30 --> 00:32:36
in 2003, because of AIDS, it's less
then 35 years.
394
00:32:36 --> 00:32:42
So it has dramatically affected the
lives of people throughout the world.
395
00:32:42 --> 00:32:48
OK. And, as you know,
I suspect you know that transmission
396
00:32:48 --> 00:32:54
for this virus occurs through direct
contact of contaminated fluids.
397
00:32:54 --> 00:33:00
Sexual contact, which is both
homosexual and heterosexual.
398
00:33:00 --> 00:33:04
As well as blood transfusion,
direct blood contact, through
399
00:33:04 --> 00:33:09
transfusion, and also needle sharing.
And sometimes occasionally organ
400
00:33:09 --> 00:33:14
donation, but that's very,
very rare. OK.
401
00:33:14 --> 00:33:21.75
So people die from AIDS because they
402
00:33:21 --> 00:33:25.25
develop infections.
And we'll talk a bit more about
403
00:33:25 --> 00:33:28.75
that in a moment.
But here's one patient who has
404
00:33:28 --> 00:33:32.25
developed an infection with a virus,
a particular type of herpes virus
405
00:33:32 --> 00:33:36
now called Kaposi's sarcoma virus.
That virus then is able to replicate
406
00:33:36 --> 00:33:40
in certain cells of the blood
vasculature and cause tumors.
407
00:33:40 --> 00:33:44
These are actually tumors. And
this individual will die from a
408
00:33:44 --> 00:33:48
disease called Kaposi's sarcoma,
a type of cancer, another example of
409
00:33:48 --> 00:33:52
a virus-associated cancer of humans.
And in this country AIDS, as you
410
00:33:52 --> 00:33:56
probably know,
has taken over as the leading killer
411
00:33:56 --> 00:34:01
of young male adults.
It was not known in the early 1980s,
412
00:34:01 --> 00:34:06
and by 1992, just ten years later
had become the major killer of young
413
00:34:06 --> 00:34:10
male adults in this country.
And, of course, likewise around the
414
00:34:10 --> 00:34:15
world. So here's the virus.
As I said, it's a retrovirus.
415
00:34:15 --> 00:34:20
Retroviruses also are enveloped.
They have glycoproteins on the
416
00:34:20 --> 00:34:25
outside, envelope glycoproteins.
They have a capsid like all viruses
417
00:34:25 --> 00:34:30
do. They have a genome.
The genome is made of RNA.
418
00:34:30 --> 00:34:34
And, as you know,
through the retroviral lifecycle,
419
00:34:34 --> 00:34:38
the RNA is converted into a DNA form.
We'll go over that next time.
420
00:34:38 --> 00:34:42
And that's accomplished by an
enzyme called reverse transcriptase
421
00:34:42 --> 00:34:46
which gets prepackaged with the
virus. Again,
422
00:34:46 --> 00:34:50
it has to be there because your
cells don't have an RNA dependent
423
00:34:50 --> 00:34:54
RNA polymerase.
So this gets prepackaged.
424
00:34:54 --> 00:34:58
The virus then infects cells.
And this, again, is a somewhat
425
00:34:58 --> 00:35:01
oversimplification.
I'll show you more details in a
426
00:35:01 --> 00:35:05
second. But the virus attaches via
glycoproteins on its surface,
427
00:35:05 --> 00:35:08
membrane proteins on the surface of
the host cell.
428
00:35:08 --> 00:35:12
In this case it's a familiar
protein to you called CD4.
429
00:35:12 --> 00:35:15
That leads to a fusion event.
So now at the plasma membrane,
430
00:35:15 --> 00:35:19
which is different from what we saw
with flu virus which happened in an
431
00:35:19 --> 00:35:22
internal membrane,
at the plasma membrane there's a
432
00:35:22 --> 00:35:26
fusion event. So now the viral
membrane fuses with the host cell
433
00:35:26 --> 00:35:30
membrane and the viral capsid can
lead into the cytoplasm.
434
00:35:30 --> 00:35:33
There's a little bit of unpackaging
that goes on. And then reverse
435
00:35:33 --> 00:35:36
transcriptase,
that enzyme that got prepackaged
436
00:35:36 --> 00:35:39
there acts on the viral genome,
which is made of RNA and converts it
437
00:35:39 --> 00:35:43
to a DNA form,
a double-stranded DNA form which is
438
00:35:43 --> 00:35:46
called a provirus.
And that provirus then gets
439
00:35:46 --> 00:35:49
integrated into the host cell genome
in a random process,
440
00:35:49 --> 00:35:53
random integration, the host cell
genome. This is also accomplished
441
00:35:53 --> 00:35:56
by a pre-packed enzyme called
integrase. Once in the genome it
442
00:35:56 --> 00:36:00
gets treated like any
old piece of DNA.
443
00:36:00 --> 00:36:03
It gets transcribed into actually
multiple different RNAs.
444
00:36:03 --> 00:36:07
They get translated into viral
proteins which come together at the
445
00:36:07 --> 00:36:10
plasma membrane and the
glycoproteins,
446
00:36:10 --> 00:36:14
the capsid proteins which
incorporate the genome,
447
00:36:14 --> 00:36:18
plus the reverse transcriptase,
and you make a new particle. OK?
448
00:36:18 --> 00:36:21
So this is more or less the
lifecycle. There is some detail
449
00:36:21 --> 00:36:25
that I want to share with you in a
moment because it's interesting.
450
00:36:25 --> 00:36:29
This is what it looks like in real
life.
451
00:36:29 --> 00:36:33
These are HIV particles budding off
the surface of an infected cell.
452
00:36:33 --> 00:36:37
They have a very characteristic
electron dense structure.
453
00:36:37 --> 00:36:41
You can actually tell it is HIV
from just the way it looks in the
454
00:36:41 --> 00:36:45
electron microscope.
And this is an HIV infected T cell.
455
00:36:45 --> 00:36:49
Now, CD4 should have rung a bell
that it's one of the proteins on the
456
00:36:49 --> 00:36:53
surface of helper T cells,
CD4 positive T cells. That is a
457
00:36:53 --> 00:36:58
major cell of infection for HIV.
And here is one such cell infected.
458
00:36:58 --> 00:37:02
And all these little blebs budding
off the surface of this cell are
459
00:37:02 --> 00:37:06
viruses getting out.
This process actually doesn't
460
00:37:06 --> 00:37:11
itself, the budding process doesn't
itself kill the T cell but,
461
00:37:11 --> 00:37:15
nevertheless, T cells, this class of
T cells dies. And,
462
00:37:15 --> 00:37:20
actually, that's a critical event in
the development of HIV-AIDS,
463
00:37:20 --> 00:37:24
the disease. We'll come to that in
a second, but let me first tell you
464
00:37:24 --> 00:37:44
one of the interesting details.
465
00:37:44 --> 00:37:48
The situation is a little more
complicated than the figure that I
466
00:37:48 --> 00:37:52
gave you on that slide.
There are two glycoproteins on the
467
00:37:52 --> 00:37:56
surface of HIV.
One of them is called GP120 for
468
00:37:56 --> 00:38:02
glycoprotein 120.
It's linked by a disulfide linkage
469
00:38:02 --> 00:38:08
to another protein called GP41.
And we now know that both of these
470
00:38:08 --> 00:38:14
proteins participate in binding and
fusion. And on the surface of the
471
00:38:14 --> 00:38:20
infected cell is CD4,
as was indicated on that slide.
472
00:38:20 --> 00:38:26
And that is the major viral
receptor that is present on helper T
473
00:38:26 --> 00:38:33
cells, CD4 positive T cells.
It's also present on macrophages.
474
00:38:33 --> 00:38:37.5
As well as certain cells in the
brain called glial cells.
475
00:38:37 --> 00:38:42
So there are CD4 positive
macrophages and glial cells.
476
00:38:42 --> 00:38:46.5
AIDS-associated dementia, which you
may know about,
477
00:38:46 --> 00:38:51
is caused by the destruction of the
glial cells in the brain.
478
00:38:51 --> 00:38:55.5
Now, there's another protein which
participates, not so much in the
479
00:38:55 --> 00:39:00
binding but in the fusion event that
allows the virus to get in.
480
00:39:00 --> 00:39:02
And this is actually a class of
proteins called chemokine
481
00:39:02 --> 00:39:10
receptors.
482
00:39:10 --> 00:39:13
There are actually multiple
chemokine receptors on your cells.
483
00:39:13 --> 00:39:17
And, in fact, different HIV forms
bind to different of these.
484
00:39:17 --> 00:39:20
But just to simplify, let's say
that there is one of these which
485
00:39:20 --> 00:39:24
binds to the GP41 portion.
And it's that binding that allows
486
00:39:24 --> 00:39:28
the virus to fuse.
If you don't have this you cannot
487
00:39:28 --> 00:39:32
fuse.
And, therefore,
488
00:39:32 --> 00:39:36
the cells are not infected.
What's interesting about that is
489
00:39:36 --> 00:39:40
two-fold. One,
it could represent a therapeutic
490
00:39:40 --> 00:39:44
target. That interaction could be a
therapeutic target.
491
00:39:44 --> 00:39:49
But it came to light in an
interesting way which was there are
492
00:39:49 --> 00:39:53
people who have been followed a long
time who lived in high-risk
493
00:39:53 --> 00:39:57
populations, drug-users or
homosexual men with multiple
494
00:39:57 --> 00:40:01
contacts with known HIV infected
people who have not themselves
495
00:40:01 --> 00:40:06
gotten HIV.
They seem to be naturally resistant
496
00:40:06 --> 00:40:11
to the development of HIV,
despite documented exposure to the
497
00:40:11 --> 00:40:17
virus. And they were studied.
And when that observation was made
498
00:40:17 --> 00:40:22
it was found that these individuals
lack the chemokine receptor.
499
00:40:22 --> 00:40:27
And if you lack the chemokine
receptor, you may have CD4 on the
500
00:40:27 --> 00:40:33
surface of your cells but you don't
have that critical co-receptor.
501
00:40:33 --> 00:40:39
And so there can be binding but no
fusion. So your cells are resistant.
502
00:40:39 --> 00:40:45
So these individuals are naturally
resistant to HIV. OK.
503
00:40:45 --> 00:40:58
So HIV infects.
504
00:40:58 --> 00:41:02
It infects a lot of T cells,
helper T cells and other cells in
505
00:41:02 --> 00:41:05
the body. Why do you get sick?
Well, as I mentioned, people get
506
00:41:05 --> 00:41:09
sick because of the loss,
the absence --
507
00:41:09 --> 00:41:19
During infection,
508
00:41:19 --> 00:41:23
the CD4 positive T cells get
eliminated. How exactly they get
509
00:41:23 --> 00:41:27
eliminated, why exactly they get
eliminated we don't yet know,
510
00:41:27 --> 00:41:31
but we know that the levels of these
cells goes down inside the
511
00:41:31 --> 00:41:35.5
infected individual.
And, as you probably remember,
512
00:41:35 --> 00:41:45
CD4 positive T cells --
513
00:41:45 --> 00:41:48
-- are required for the development
of these cells.
514
00:41:48 --> 00:41:55
So if you don't have CD4 positive T
515
00:41:55 --> 00:41:57
cells you cannot make antibody
producing cells.
516
00:41:57 --> 00:42:00
You cannot make functional
antibodies.
517
00:42:00 --> 00:42:05
And, to some extent,
they're also required for the
518
00:42:05 --> 00:42:10
development of cytotoxic T cells.
So that part of the immune system
519
00:42:10 --> 00:42:15
is also compromised.
So the virus wipes out these cells
520
00:42:15 --> 00:42:20
and, therefore,
the immune system crashes.
521
00:42:20 --> 00:42:26
And that's why it's called AIDS for
acquired immunodeficiency.
522
00:42:26 --> 00:42:32
Acquired because it comes through an
523
00:42:32 --> 00:42:36
infectious agent.
Immunodeficiency because your
524
00:42:36 --> 00:42:40
immune system crashes.
And when your immune system crashes
525
00:42:40 --> 00:42:44
you cannot fight infections.
And AIDS patients largely die
526
00:42:44 --> 00:42:48
because they get one or another type
of infection.
527
00:42:48 --> 00:42:54.75
So this is a graph which shows the
528
00:42:54 --> 00:42:58.25
time course of HIV infection.
And it kind of makes the point that
529
00:42:58 --> 00:43:01
T cells go away.
Shortly after you are infected,
530
00:43:01 --> 00:43:04
the level of HIV in your blood goes
way, way up, as you can see here.
531
00:43:04 --> 00:43:08
It spikes in the first several
months after your infection.
532
00:43:08 --> 00:43:11
Some people actually manifest that
aspect of the disease.
533
00:43:11 --> 00:43:14
Many don't so they don't know that
they have such a high concentration
534
00:43:14 --> 00:43:17
of virus. And,
importantly, your body deals with it
535
00:43:17 --> 00:43:20
so you make antibodies,
in black. You make anti-HIV
536
00:43:20 --> 00:43:24
antibodies. And,
remember, it's these that are
537
00:43:24 --> 00:43:27
detected by the AIDS test.
If you've been exposed then you
538
00:43:27 --> 00:43:31
make antibodies.
And they stick around so that you
539
00:43:31 --> 00:43:35
know that you've been infected.
Likewise, T cells, cytotoxic T
540
00:43:35 --> 00:43:40
cells, CD8 positive T cells go up.
And that controls the level of the
541
00:43:40 --> 00:43:45
virus. And it stays low for a while,
but after a while,
542
00:43:45 --> 00:43:49
because of the affects on the CD4
positive T cells,
543
00:43:49 --> 00:43:54
the other cells in the immune system
are no longer sustained so the B
544
00:43:54 --> 00:43:59
cells start to drop off and the T
cells start to drop off.
545
00:43:59 --> 00:44:02
And now you're starting to lose the
battle against the HIV,
546
00:44:02 --> 00:44:06
so the levels of HIV go up.
And as they go up, you lose more
547
00:44:06 --> 00:44:09
CD4 positive T cells and the
situation gets worse and worse.
548
00:44:09 --> 00:44:13
So after a while, usually in the
several years out time point,
549
00:44:13 --> 00:44:17
your immune system is now no longer
functional and you're very
550
00:44:17 --> 00:44:20
susceptible to opportunistic
infections. So AIDS patients will
551
00:44:20 --> 00:44:24
develop infections,
and the infections will progress in
552
00:44:24 --> 00:44:28
a way that won't happen
in a healthy person.
553
00:44:28 --> 00:44:32
Certain bacterial infections that
you would clearly very easily take
554
00:44:32 --> 00:44:37
hold and can cause major problems.
Kaposi's sarcoma is caused by
555
00:44:37 --> 00:44:42
infection of this particular virus.
AIDS patients are very susceptible
556
00:44:42 --> 00:44:47
to tuberculosis,
this particular fungal infection,
557
00:44:47 --> 00:44:51
certain other viral infections. And
in aggregate, the exposure to these
558
00:44:51 --> 00:44:56
various infectious agents and the
damage that they're causing leads to
559
00:44:56 --> 00:45:01
the death of the patient. OK.
So that's bad news.
560
00:45:01 --> 00:45:06
And obviously it's have major and
devastating consequences around the
561
00:45:06 --> 00:45:11
world. So what can we do about it?
Well, there is some good news here.
562
00:45:11 --> 00:45:33
There are antiviral therapies.
563
00:45:33 --> 00:45:44
Remember that viruses largely use
564
00:45:44 --> 00:45:48
your enzymes. And you cannot make
good drugs against your own enzymes
565
00:45:48 --> 00:45:52
for treatment of a viral disease,
but I've told you about one viral
566
00:45:52 --> 00:45:56
protein to which you might be able
to make drugs. And
567
00:45:56 --> 00:46:04
indeed we have.
568
00:46:04 --> 00:46:10
HIV has an RNA genome that gets
converted to a DNA form by an enzyme
569
00:46:10 --> 00:46:17
reverse transcriptase.
There have been drugs produced that
570
00:46:17 --> 00:46:23
block that enzyme.
And you've probably heard of the
571
00:46:23 --> 00:46:29
drug AZT.
There are other drugs like
572
00:46:29 --> 00:46:33
dideoxyinosine and dideoxycytosine
that likewise bind to and block the
573
00:46:33 --> 00:46:37
activity of this enzyme.
They actually cause chain
574
00:46:37 --> 00:46:42
termination in the same way that DNA
sequencing works.
575
00:46:42 --> 00:46:46
And they work because this enzyme
is sensitive to these drugs at
576
00:46:46 --> 00:46:51
concentrations where your
polymerases are not,
577
00:46:51 --> 00:46:55
so that gives you some selected
effect in the treatment of the virus.
578
00:46:55 --> 00:47:00
And these agents,
when used singly, work for a while.
579
00:47:00 --> 00:47:04
And then the virus becomes resistant
and comes roaring back.
580
00:47:04 --> 00:47:08
How does it become resistant?
It becomes resistant through
581
00:47:08 --> 00:47:13
mutation, exactly the way cancer
cells become resistant to targeted
582
00:47:13 --> 00:47:17
therapies. Variant forms of HIV
arise which have slightly altered
583
00:47:17 --> 00:47:22
reverse transcriptases that now
won't bind to AZT or DDI or DDC.
584
00:47:22 --> 00:47:26
And the problem is very, very
serious because viruses,
585
00:47:26 --> 00:47:31
RNA viruses in particular are highly
mutagenic.
586
00:47:31 --> 00:47:36
They create variant forms at high
frequency. An HIV infected person
587
00:47:36 --> 00:47:41
makes ten to the tenth viral
particles a day.
588
00:47:41 --> 00:47:46
At a mutation rate of ten to the
minus fifth, that would mean ten to
589
00:47:46 --> 00:47:52
the fifth variants of every
nucleotide. OK?
590
00:47:52 --> 00:47:57
So variants come up frequently that
are resistant to this
591
00:47:57 --> 00:48:14
therapy. Oops.
592
00:48:14 --> 00:48:24
Fortunately, there are alternatives.
The viral RNA gets translated into
593
00:48:24 --> 00:48:40
a large polyprotein --
594
00:48:40 --> 00:48:44
-- which is processed by a viral
protease encoded by the virus into
595
00:48:44 --> 00:48:48
different mature proteins.
Reverse transcriptase is one of
596
00:48:48 --> 00:48:53
them. The integrase that I
mentioned is another.
597
00:48:53 --> 00:48:57
And there are others.
This is a viral protein,
598
00:48:57 --> 00:49:02
a viral enzyme.
And so, in theory,
599
00:49:02 --> 00:49:06
it's possible to make inhibitors
against the protease.
600
00:49:06 --> 00:49:11
And that's been successful.
Several companies have made
601
00:49:11 --> 00:49:15
inhibitors that will specifically
inhibit the viral protease that work
602
00:49:15 --> 00:49:20
well. They work for a while and
then resistant forms arise for
603
00:49:20 --> 00:49:24
exactly the same reason I said.
You can create versions of protease
604
00:49:24 --> 00:49:29
which still work but won't bind the
drug. OK? So what do you do?
605
00:49:29 --> 00:49:34
Does anybody know what you do to
overcome this problem?
606
00:49:34 --> 00:49:46
You put the drugs together.
607
00:49:46 --> 00:49:54
So currently HIV patients,
608
00:49:54 --> 00:49:58
in this country anyway, and
hopefully soon around the world will
609
00:49:58 --> 00:50:02
get triple therapy when
they're diagnosed.
610
00:50:02 --> 00:50:08
And triple therapy includes two
reverse transcriptase inhibitors and
611
00:50:08 --> 00:50:18
one protease inhibitor.
612
00:50:18 --> 00:50:22
Since the development of resistance
against each of these agents is
613
00:50:22 --> 00:50:26
independent of the other,
to get resistance to all three is
614
00:50:26 --> 00:50:30
the product of the individual
frequency.
615
00:50:30 --> 00:50:35
So I said that the frequency of
developing resistance to any one is
616
00:50:35 --> 00:50:40
ten to the minus fifth.
To be resistant to all three would
617
00:50:40 --> 00:50:45
occur at ten to the minus fifteenth,
which is highly, highly unlikely.
618
00:50:45 --> 00:50:50
And so people tend not to develop
resistance to all three and,
619
00:50:50 --> 00:50:55
therefore, triple therapy tends to
keep the virus in-check for
620
00:50:55 --> 00:51:00
sustained periods of time.
As you probably know, this works.
621
00:51:00 --> 00:51:03.75
The fear is that it is starting not
to work. And there are starting to
622
00:51:03 --> 00:51:07.5
be some resistant forms developing
here and they are starting to make
623
00:51:07 --> 00:51:11.25
their way into the population,
so we're going to have to develop
624
00:51:11 --> 00:51:15
even better and more different
inhibitors to now combat these
625
00:51:15 --> 00:51:18.75
variant forms.
Before I let you go,
626
00:51:18 --> 00:51:22.5
the last thing I wanted to mention,
and I'll just throw it out there and
627
00:51:22 --> 00:51:26.25
you can think about it,
is that what we'd really like to
628
00:51:26 --> 00:51:30
return to for HIV is what
we can do for polio.
629
00:51:30 --> 00:51:34.5
We'd like to be able to treat people
routinely in this country or out in
630
00:51:34 --> 00:51:39
the field in more distant regions
with an effective vaccine,
631
00:51:39 --> 00:51:43.5
which isn't possible today.
We don't have one for HIV. You
632
00:51:43 --> 00:51:48
might think about what you would do
to make one and why it has been so
633
00:51:48 --> 00:51:51
hard. And I'll touch
on that next time.